The oncogene Ets-1 is over-expressed in a large proportion of oral squamous cell cancers and expression of Ets- 1 is highly-correlated with tumor stage and the presence of lymph node metastases. Ets-1 is known to regulate the expression genes involved in tumor invasion and neo-angiogenesis, including matrix metalloproteases and endothelial cell growth factor receptors. In addition, Ets-1 has been implicated in controlling the expression of genes important for cell cycle progression and for regulating apoptosis. Finally, gene-targeted Ets-1 deficient mice demonstrate a role for Ets-1 in limiting cellular differentiation. Thus, Ets-1 may influence tumor progression in multiple ways by promoting invasion, angiogenesis and proliferation while at the same time limiting apoptosis and preventing terminal differentiation. To better define the precise roles of Ets-1 in oral tumor formation and progression, we have generated a transgenic mouse model system in which expression of Ets-1 can be induced in the differentiated cells of the oral epithelium. Upon Ets-1 induction, these mice exhibit dramatic changes in the epithelium including increased proliferation, blocked terminal differentiation and malignant conversion. We now propose to use this mouse model to identify the mechanisms by which Ets-1 regulates important pathways involved in oral cancer formation. These studies will be supplemented by complementary analyses using cultured oral keratinocytes. The results of our experiments will help to determine whether therapies directed against Ets-1 would be clinically useful in treating aggressive oral squamous cell carcinomas. [unreadable] [unreadable] Oral squamous cell carcinoma (OSCC) is a neoplasm that arises in the stratified squamous epithelium of the mouth. Five-year survival rates for patients with oral squamous cell cancers have not changed much in the last 20 years, suggesting that new approaches to therapy are needed. Our studies are designed to identify the role of the oncogene Ets-1 in regulating OSCC initiation and progression, with the eventual hope of developing novel strategies to target Ets-1 activity and regulate tumor cell growth. [unreadable] [unreadable] [unreadable]